Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects
Open accessAbstract
Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ΔFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ΔFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that ΔFosB binds the CaMKIIα gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ΔFosB to the CaMKIIα promoter and reduces CaMKII expression in NAc, despite the fact that ΔFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter, which blocks the ΔFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.
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Higher H3K9me2 levels at the CaMKIIα promoter and inhibition of CaMKIIα were found in MDD and in mice following antidepressant administration.
“higher H3K9me2 levels at the calmodulin-dependent protein kinase II α (CaMKIIα) promoter and inhibition of CaMKIIα were found in MDD and mice following antidepressant administration.171”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [171]
ΔFosB binds to the CaMKIIα promoter.
“ΔFosB binds to the promoter of CaMKIIα and CSDS enhances its binding enrichment on this promoter (88).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [88]
Overexpressing CaMKII in the nucleus accumbens blocks fluoxetine's antidepressant effect in stressed mice.
“Chronic treatment with the SSRI fluoxetine reduces binding of ΔFosB to the CaMKII promoter and NAc overexpression of CaMKII blocks the antidepressant efficacy of fluoxetine in stressed mice.”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [88]
Chronic social defeat stress increases ΔFosB binding at the CaMKIIα promoter.
“ΔFosB binds to the promoter of CaMKIIα and CSDS enhances its binding enrichment on this promoter (88).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [88]
Chronic fluoxetine treatment reduces ΔFosB binding to the CaMKII promoter.
“Chronic treatment with the SSRI fluoxetine reduces binding of ΔFosB to the CaMKII promoter and NAc overexpression of CaMKII blocks the antidepressant efficacy of fluoxetine in stressed mice.”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [88]
These effects occur through an epigenetic mechanism that lowers acetylation and raises H3meK9 methylation.
“These effects are through an epigenetic mechanism of reducing acetylation and increasing H3meK9 methylation.”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [88]
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“In addition, higher H3K9me2 levels at the calmodulin-dependent protein kinase II α (CaMKIIα) promoter and inhibition of CaMKIIα were found in MDD and mice following antidepressant administration.(171) The activation of H3K27me3 in the NAc of mice exposed to social defeat stress inhibits the expression of RASrelated C3…”
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- Authors
- Robison, A. J., Vialou, V., Sun, H.-S., Labonte, B., A Golden, S., Dias, C., Turecki, G., Tamminga, C., Russo, S., Mazei-Robison, M., & Nestler, E. J.
- Affiliations
- Michigan State University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Douglas Mental Health University Institute (CA)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Robison, A J
- Nestler, Eric J
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2013-11-15
- Volume
- 39
- Issue
- 5
- Pages
- 1178-1186
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3957112
- OpenAlex
- W2008826113
- Cited by
- 105
- References
- 36
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 14 · 2016: 8 · 2015: 11 · 2014: 7
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (P50MH086890, P50MH096890, R01MH051399)
- National Institute on Drug Abuse (R01DA007359)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- fluoxetine, CaMKIIα, ΔFosB, nucleus accumbens, chronic social defeat stress, depression, antidepressant mechanism, epigenetic regulation, histone acetylation, H3K9me2, chromatin binding, CaMKII inhibition
- MeSH terms
- Animals, Depressive Disorder, Female, Fluoxetine, Humans, Male, Middle Aged, Nucleus Accumbens, Promoter Regions, Genetic, RNA, Messenger, Social Behavior, Stress, Psychological, Proto-Oncogene Proteins c-fos, Antidepressive Agents, Second-Generation, Epigenesis, Genetic, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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